Process for the preparation of 6-methyl-3,4-dihydro-1,2,3-oxathiazin-4-one 2,2-dioxide and its non-toxic salts

ABSTRACT

6-Methyl-3,4-dihydro-1,2,3-oxathiazin-4-one 2,2-dioxide is prepared by 
     (a) reacting, in an inert organic solvent, a salt of sulfamic acid, which is at least partially soluble therein, with at least approximately the equimolar amount of an acetoacetylating agent, in the presence of an amine or phosphine catalyst, and by cyclizing the acetoacetamide-N-sulfonate which is formed in this reaction, or the free sulfonic acid, 
     (b) by the action of at least approximately the equimolar amount of SO 3 , where appropriate in an inert inorganic or organic solvent, to give 6-methyl-3,4-dihydro-1,2,3-oxathiazin-4-one 2,2-dioxide, which is produced in the form of the acid in this reaction; 
     it is possible, if desired, to obtain from the acid form 
     (c) the appropriate salts by neutralization with bases. The non-toxic salts - in particular the potassium salt - are valuable synthetic sweeteners.

This application is a division of application Ser. No. 714,177 filedMar. 20, 1985 now U.S. Pat. No. 4,607,100.

6-Methyl-3,4-dihydro-1,2,3-oxathiazin-4-one 2,2-dioxide is the compoundof the formula ##STR1## As a consequence of the acidic hydrogen on thenitrogen atom, the compound is able to form salts (with bases). Thenon-toxic salts, such as, for example, the Na, the K and the Ca salt,can, because of their sweet taste, which is intense in some cases, beused as sweeteners in the foodstuffs sector, the K salt ("Acesulfame K"or just "Acesulfame") being of particular importance.

A number of different processes is known for the preparation of6-methyl-3,4-dihydro-1,2,3-oxathiazin-4-one 2,2-dioxide and itsnon-toxic salts; see Angewandte Chemie 85, Issue 22 (1973) pages 965 to73, corresponding to International Edition Vol. 12, No. 11 (1973), pages869-76. Virtually all the processes start from chloro-or fluorosulfonylisocyanate (XSO₂ NCO with X=Cl or F). The chloro- or fluorosulfonylisocyanate is then reacted with monomethylacetylene, acetone,acetoacetic acid, tert.-butyl acetoacetate or benzyl propenyl ether(usually in a multistage reaction) to give acetoacetamide-N-sulfonylchloride or fluoride which, under the action of bases (such as, forexample, methanolic KOH), is cyclized and provides the correspondingsalts of 6-methyl-3,4-dihydro-1,2,3-oxathiazin-4-one 2,2-dioxide. Wheredesired, the free oxathiazinone can be obtained from the salts in acustomary manner (with acids).

Another process for the preparation of the oxathiazinone intermediateacetoacetamide-N-sulfonyl fluoride starts from sulfamoyl fluoride H₂NSO₂ F, which is the partial hydrolysis product of fluorosulfonylisocyanate (German Offenlegungsschrift No. 2,453,063). The fluoride ofsulfamic acid H₂ NSO₂ F is then reacted with an approximately equi-molaramount of the acetoacetylating agent diketene, in an inert organicsolvent, in the presence of an amine, at temperatures between about -30°and 100° C.; the reaction takes place in accordance with the followingequation (with triethylamine as the amine): ##STR2##

Acetoacetamide-N-sulfonyl fluoride

The acetoacetamide-N-sulfonyl fluoride is then cyclized in a customarymanner using a base, for example using methanolic KOH, to the sweetener:##STR3##

Although some of the known processes provide quite satisfactory yieldsof 6-methyl 3,4-dihydro-1,2,3-oxathiazin-4one 2,2-dioxide and itsnon-toxic salts (up to about 85% of theory based on the startingsulfamoyl halide), they are still in need of improvement, particularlyfor industrial purposes, because of the necessity of using chloro- orfluorosulfonyl isocyanate, which are not very easy to obtain, asstarting materials; this is because the preparation of the chloro- andfluorosulfonyl isocyanate requires considerable precautionary measuresand safety arrangements by reason of the starting materials (HCN, Cl₂,SO₃ and HF), some of which are rather unpleasant to handle. Thepreparation of the chloro- and fluorosulfonyl isocyanate are based onthe following reaction equations:

    HCN+Cl.sub.2 →ClCN+HCl

    ClCN+SO.sub.3 →ClSO.sub.2 NCO

    ClSO.sub.2 NCO+HF→FSO.sub.2 NCO+HCl

Replacement of the sulfamoyl fluoride in the process according to theabovementioned German Offenlegungsschrift No. 2,453,063 by, for example,the considerably more easily obtainable (for example from NH₃ +SO₃)sulfamic acid H₂ NSO₃ H or its salts hardly appeared promising becausethe reaction of Na sulfamate H₂ NSO₃ Na with diketene in anaqueous-alkaline solution does not provide any reaction product whichcan be isolated pure. Rather, it has been possible to obtain the 1:1adduct, which is probably at least partially formed in this reaction,only in the form of the coupling product with 4-nitrophenyldiazoniumchloride, as a pale yellow dyestuff; see Ber. 83 (1950), pages 551-558,in particular page 555, last paragraph before the description of theexperiments, and page 558, last paragraph: ##STR4##

Moreover, the acetoacetamide-N-sulfonic acid has otherwise beenpostulated only, or also, as an intermediate in the decomposition of6-methyl-3,4-dihydro-1,2,3-oxathiazin-4-one 2,2-dioxide during boilingin aqueous solution; see the literature cited in the introduction,Angew. Chemie (1973) loc. cit.: ##STR5##

Thus, because the state of the art processes for the preparation of6-methyl-3,4-dihydro-1,2,3-oxathiazin-4-one 2,2-dioxide and itsnon-toxic salts are, in particular, not entirely satisfactory for beingcarried out on an industrial scale, in particular as a result of thenecessity to use starting materials which are not very straightforwardto obtain, the object was to improve the known processes appropriatelyor to develop a new improved process.

This object has been achieved according to the invention by amodification of the process of German Offenlegungsschrift No. 2,453,063(mainly replacement of the sulfamoyl fluoride in the known process bysalts of sulfamic acid) followed by ring closure of the resultingacetoacetylation product using SO₃. Thus, the invention relates to aprocess for the preparation of6-methyl-3,4-dihydro-1,2,3-oxathiazin-4-one 2,2-dioxide and itsnon-toxic salts by

(a) reaction of a sulfamic acid derivative with at least anapproximately equimolar amount of an acetoacetylating agent in an inertorganic solvent, where appropriate in the presence of an amine orphosphine catalyst, to give an acetoacetamide derivative and

(b) ring closure of the acetoacetamide derivative; the process comprisesthe use as the sulfamic acid derivative in step a) of a salt of sulfamicacid which is at least partially soluble in the inert organic solventused, the ring closure in step (b) of acetoacetamide-Nsulfonate or ofthe free acetoacetamide-N-sulfonic acid, which is formed in the firststep, by the action of at least an approximately equimolar amount ofSO₃, wherein appropriate in an inert inorganic or organic solvent, toform the ring of 6-methyl-3,4-dihydro-1,2,3-oxathiazin-4-one2,2-dioxide, and then the neutralization with a base of the productwhich results from this in the acid form, where appropriate in anadditonal (step c).

The reaction equations on which the process is based are as follows(with diketene as the acetoacetylating agent): ##STR6##

The process starts from starting materials which are straightforward toobtain and of low cost and it is extremely straightforward to carry out.The yields are about 90 to 100% of theory in (step a) (based on thestarting sulfamate),

about 70 to 95% of theory in (step b) (based on theacetoacetamide-N-sulfonate) and

about 100% of theory in (step c) (based on the oxathiazinone in the acidform),

so that the yields resulting for the overall process are between about65 and 95% of theory. Thus, compared with the state of the artprocesses, the invention represents a considerable advance.

It is extremely surprising that the reaction between sulfamate andacetoacetylating agent to give acetoacetamide-N-sulfonate by (step a)takes place smoothly because, on the basis of literature reference Ber.83 (1950) loc. cit., according to which the reaction between Nasulfamate and diketene in aqueous-alkaline solution is apparently onlyrather undefined, a good yield and a 1:1 reaction product, which couldbe isolated pure without difficulty, was hardly to be expected fromsulfamic acid or its salts and acetoacetylating agents.

It is equally surprising that the ring closure ofacetoacetamide-N-sulfonate or of the free sulfonic acid, using SO₃ in(step b) of the process, takes place exceedingly well, because theelimination of water or bases (MOH) taking place with ring closure inthis step either does not occur or, at any rate, virtually does notoccur with other agents which eliminate water or bases, such as, forexample, P₂ O₅, acetic anhydride, trifluoroacetic anhydride, thionylchloride etc.

In detail, the process according to the invention is carried out asfollows:

(Step a):

It is possible to use as the acetoacetylating agent the compounds knownfor acetoacetylations such as, for example, acetoacetyl chloride anddiketene; the preferred acetoacetylating agent is diketene.

The amount of acetoacetylating agent used should be at leastapproximately equimolar (related to the reactant sulfamate). It ispreferable to use an excess of up to about 30 mol-%, in particular anexcess of only up to about 10 mol-%. Excesses greater than about 30mol-% are possible, but entail no advantage.

Suitable inert organic solvents are virtually all organic solvents whichdo not react in an undesired manner with the starting materials andfinal products or, where appropriate, the catalysts in the reaction, andwhich also have the ability to dissolve, at least partially, salts ofsulfamic acid. Thus, the following organic solvents may be mentioned inthis context as suitable and preferred:

halogenated aliphatic hydrocarbons, preferably those having up to 4carbon atoms such as, for example, methylene chloride, chloroform,1,2-dichlorethane, trichloroethylene, tetrachloroethylene,trichlorofluoroethylene etc.;

aliphatic ketones, preferably those having 3 to 6 carbon atoms such as,for example, acetone, methyl ethyl ketone etc.;

aliphatic ethers, preferably cyclic aliphatic ethers having 4 or 5carbon atoms such as, for example, tetrahydrofuran, dioxane etc.;

lower aliphatic carboxylic acids, preferably those having 2 to 6 carbonatoms such as, for example, acetic acid, propionic acid etc.;

aliphatic nitriles, preferably acetonitrile;

N-alkyl-substituted amides of carbonic acid and lower aliphaticcarboxylic acids, preferably amides having up to 5 carbon atoms such as,for example, tetramethylurea, dimethylformamide, dimethylacetamide,N-methylpyrrolidone etc.;

aliphatic sulfoxides, preferably dimethyl sulfoxide, and

aliphatic sulfones, preferably sulfolane ##STR7##

Particularly preferred solvents from the above list are methylenechloride, 1,2-dichloroethane, acetone, glacial acetic acid anddimethylformamide, especially methylene chloride.

The solvents can be used either alone or in a mixture.

The ratio of the amounts of the reaction starting materials to thesolvent can vary within wide limits; in general, the weight ratio isabout 1:(2-10). However, other ratios are also possible.

ln principle, the amine and phosphine catalysts which can be used areall amines and phosphines whose use as catalysts for addition reactionsof diketene is known. These are mainly tertiary amines and phosphines(still) having nucleophilic characteristics.

Those which are preferred in the present case are tertiary amines andphosphines in which each N or P atom has up to 20, in particular only upto 10, carbon atoms. The following tertiary amines may be mentioned asexamples:

Trimethylamine, triethylamine, tri-n-propylamine, triisopropylamine,tri-n-butylamine, triisobutylamine, tricyclohexylamine,ethyldiisopropylamine, ethyldicyclohexylamine, N,N-dimethylaniline,N,N-diethylaniline, benzyldimethylamine, pyridine, substitutedpyridines, such as picolines, lutidines, collidines or methyl ethylpyridines, N-methylpiperidine, N-ethylpiperidine, N-methylmorpholine,N,N'-dimethylpiperazine, 1,5-diazabicyclo[4.3.0]non-5-ene,1,8-diazabicyclo[5.4.0]undec-7-ene, alsotetramethylhexamethylenediamine, tetramethylethylenediamine,tetramethylpropylenediamine, tetramethylbutylenediamine, as well as1,2-dimorpholylethane, pentamethyldiethylenetriamine,pentaethyldiethylenetriamine, pentamethyldipropylenetriamine,tetramethyldiaminomethane, tetrapropyldiaminomethane,hexamethyltriethylenetetramine, hexamethyltripropylenetetramine,diisobutylenetriamine or triisopropylenetetramine.

A particularly preferred amine is triethylamine.

Examples of tertiary phosphines are methyldiphenylphosphine,triphenylphosphine, tributylphosphine etc.

The amount of catalyst is normally up to about 0.1 mole per mole ofsulfamate. Larger amounts are possible, but entail hardly anyadvantages. In principle, reaction step a) of the process according tothe invention also takes place without catalyst; however, the catalystacts to accelerate the reaction and is thus advantageous.

The sulfamic acid salts to be used for the process must be at leastpartially soluble in the inert organic solvent. This requirement is metby, preferably, lithium, NH₄ and the primary, secondary, tertiary andquaternary ammonium salts of sulfamic acid. In turn, the ammonium saltswhich are preferred are those whose ammonium ion contains not more thanabout 20, in particular not more than about 10, carbon atoms. Examplesof ammonium salts of sulfamic acid are the salts having the followingammonium ions: ##STR8##

A particularly preferred sulfamate is the triethylammonium salt.

The salts are usually obtained in a manner known per se byneutralization of sulfamic acid with LiOH, NH₃ or the appropriate aminesor quaternary ammonium hydroxide solutions, followed by removal ofwater. The base is preferably added in a stoichiometric excess (based onthe sulfamic acid) of up to about 30 mol-%, in particular up to onlyabout 15 mol-%. In addition, it is also preferred for the organic moietyin the ammonium ion to be identical to the organic moiety in the aminecatalyst (for example use of triethylammonium sulfamate as the sulfamicacid salt and of triethylamine as the catalyst). In the case of saltswith NH₃ and primary and secondary amines, a stoichiometric amount ofthe amine component is preferably used, and the catalyst added is aweakly basic tert.-amine, such as, for example, pyridine.

In general, the reaction temperature is selected to be in a rangebetween about -30° and +50° C., preferably between about 0° and 25° C.

The reaction is normally carried out under atmospheric pressure. Thereaction time can vary within wide limits; in general, it is betweenabout 0.5 and 12 hours. The reaction can be carried out either byinitial introduction of the sulfamic acid salt and metering in ofdiketene, or by initial introduction of diketene and metering in of thesulfamic acid salt, or by initial introduction of diketene and sulfamicacid and metering in of the base or, for example, by metering into thereaction chamber both reactants simultaneously, it being possible forthe inert organic solvent either also to be initially introduced or tobe metered in together with the reactants.

After the reaction is complete, for the isolation of the reactionproduct the solvent is removed by distillation and the residue (mainlyacetoacetamide-N-sulfonate) is recrystallised from a suitable solventsuch as, for example, acetone, methyl acetate or ethanol. The yields areabout 90 to 100% of theory.

The Li and ammonium acetoacetamide-N-sulfonates are new compounds. Theyhave the formula ##STR9## in which M.sup.⊕ =Li.sup.⊕ or

N.sup.⊕ R¹ R² R³ R⁴

with R¹, R², R³ and R⁴, independently of one another, being H or organicradicals,

preferably H or C₁ -C₈ -alkyl, C₆ -C₁₀ -cycloalkyl, -aryl and/or-aralkyl.

The total number of carbon atoms in the ammonium ion in the ammoniumsalts is preferably not more than about 20, in particular not more thanabout 10.

The free acetoacetamide-N-sulfonic acid can, if desired, be obtainedfrom the acetoacetamide-N-sulfonate by customary processes.

(Step b):

The acetoacetamide-N-sulfonate (or, where appropriate, the free acid)obtained in step a) is then cyclized in step b) using at least anapproximately equimolar amount of SO₃, where appropriate in an inertinorganic or organic solvent. The SO₃ is generally used in an up toabout 20-fold, preferably about 3- to 10-fold, in particular about 4- to7-fold, molar excess based on the acetoacetamide-N-sulfonate (or thefree acid). It can be added to the reaction mixture either in the solidor the liquid form or by condensing in SO₃ vapor. Normally however, asolution of SO₃ in concentrated sulfuric acid, liquid SO₂ or an inertorganic solvent is used. It is also possible to use compounds whicheliminate SO₃. Although, in principle, it is possible to carry out thereaction without solvent, nevertheless it is preferable to carry it outin an inert inorganic or organic solvent. Suitable inert inorganic ororganic solvents are those liquids which do not react in an undesiredmanner with SO₃ or the starting materials or final products of thereaction. Thus, because of the considerable reactivity of, inparticular, SO₃ l only relatively few solvents are suitable for thispurpose. Preferred solvents are:

Inorganic solvents: liquid SO₂ ;

organic solvents: halogenated aliphatic hydrocarbons, preferably havingup to 4 carbon atoms, such as, for example, methylene chloride,chloroform, 1,2-dichloroethane, trichloroethylene, tetrachloroethylene,trichlorofluoroethylene etc.;

esters of carbonic acid with lower aliphatic alcohols, preferably withmethanol or ethanol; nitroalkanes, preferably having up to 4 carbonatoms, in particular nitromethane; alkyl-substituted pyridines,preferably collidine; and aliphatic sulfones, preferably sulfolane.

It is possible to use the organic solvents either alone or in a mixture.

Particularly preferred solvents are liquid SO₂ and methylene chloride.

The amount of inert solvent used is not critical. When a solvent isused, it is merely necessary to ensure adequate solution of thereactants; the upper limit of the amount of solvent is determined byeconomic considerations.

In a preferred embodiment of the process according to the invention thesame solvent is used in both (step a) and step (b); this is preferably ahalogenated aliphatic hydrocarbon, in particular methylene chloride.This is because, in this case, the solution obtained in (step a) can,without isolation of the acetoacetamide-N-sulfonate, be used immediatelyfor (step b).

The reaction temperature in (step b) is normally between about -70° and+175° C., preferably between about -40° and +10° C.

(Step b) resembles step a) in that it is normally carried out only underatmospheric pressure.

The reaction time can be up to about 10 hours.

The reaction can be carried out in such a manner that theacetoacetamide-N-sulfonate (or the free acid) is, where appropriate insolution, introduced and SO₃ where appropriate in the dissolved form, ismetered in, or both reactants are simultaneously transferred into thereaction chamber, or SO₃ is initially introduced and theacetoacetamide-N-sulfonate (or the free acid) is added.

It is preferable initially to introduce part of the SO₃ whereappropriate in solution, and then to meter in, either continuously or inportions, acetoacetamide-N-sulfonate (or the free acid) and SO₃ whereappropriate in the dissolved form.

Working-up is carried out in a customary manner. In the preferred casewhere methylene chloride is used as the reaction medium, working-up canbe carried out as follows, for example: to the solution containing SO₃are added about 10 times the molar amount (based on SO₃ ) of ice orwater. This brings about phase separation: the6-methyl-3,4-dihydro-1,2,3-oxathiazin-4one 2,2-dioxide which has formedis present mainly in the organic phase. The fractions still present inthe aqueous sulfuric acid can be obtained by extraction with an organicsolvent such as, for example, methylene chloride or an organic ester.

Otherwise, after the addition of water, the reaction solvent is removedby distillation, and the 6-methyl3,4-dihydro-1,2,3-oxathiazin-4-one2,2-dioxide which remains in the sulfuric acid of reaction is extractedwith a more suitable solvent. Suitable solvents are those which aresufficiently stable towards sulfuric acid and which have a satisfactorydissolving capacity; in addition, the reaction product should have inthe solvent system a partition coefficient which is favorable for theisolation. Not only halogenated hydrocarbons but also esters of carbonicacid such as, for example dimethyl carbonate, diethyl carbonate andethylene carbonate, or esters of organic monocarboxylic acids such as,for example, isopropyl formate and isobutyl formate, ethyl acetate,isopropyl acetate, butyl acetate, isobutyl acetate and neopentylacetate, or esters of dicarboxylic acids or amides which are immisciblewith water, such as, for example, tetrabutylurea, are suitable.Isopropyl acetate and isobutyl acetate are particularly preferred.

The combined organic phases are dried with, for example, Na₂ SO₄, andare evaporated. Any sulfuric acid which has been carried over in theextraction can be removed by appropriate addition of aqueous alkali tothe organic phase. For this purpose, dilute aqueous alkali is added tothe organic phase until the pH reached in the aqueous phase is thatshown by pure 6-methyl-3,4-dihydro1,2,3-oxathiazin-4-one 2,2-dioxide atthe same concentration in the same two-phase system of extracting agentand water. When it is intended to obtain the free compound, thisundergoes additional purification in a customary manner (preferably byrecrystallization). The yield is between about 70 and 95% of theorybased on acetoacetamide-N-sulfonate (or the free acid).

If, however, it is intended to obtain a non-toxic salt of6-methyl-3,4-dihydro-1,2,3-oxathiazin-4-one 2,2dioxide, neutralization(step c) is also carried out.

For this purpose, the oxathiazinone compound produced in the acid formin (step b) is neutralized with an appropriate base in a customarymanner. With this in view, for example the organic phases which havebeen combined, dried and evaporated at the end of (step b) areneutralized in suitable organic solvents such as, for example, alcohols,ketones, esters or ethers, or in water, using an appropriate base,preferably using a potassium base such as, for example, KOH, KHCO₃, K₂CO ₃, K alcoholates etc. Alternatively, the oxathiazinone compound isneutralized and extracted directly from the purified organic extractionphase (step b) using an aqueous potassium base. The oxathiazinone saltthen precipitates out, where appropriate after evaporation of thesolution, in the crystalline form, and it can also be recrystallized forpurification.

The yield in the neutralization step is virtually 100%.

Both the overall process according to the invention, consisting ofprocess steps (a), (b) and (c), and the individual process steps (a) and(b) are new and considerably advantageous.

The Examples which follow are intended to illustrate the inventionfurther. The (invention) examples of carrying out process (steps a), (b)and (c) are followed by a comparison example which shows thatacetoacetamide-N-sulfonates do not cyclize with agents which eliminatewater or bases other than SO₃ , in this case P₂ O₅.

(A) Examples of carrying out process step a: EXAMPLE 1 ##STR10## 9.7 g(0.1 mol) of sulfamic acid were added to a solution of 12 ml (0.125 mol)of trimethylamine in 100 ml of glacial acetic acid, and the mixture wasstirred until dissolution was complete. Then, 8 ml (0.104 mol) ofdiketene were added dropwise, while cooling at 25-30°. After 16 hours,the reaction product was precipitated by slow addition of ether and wasfiltered off with suction.

IR (KBr) 1045, 1240, 1470, 1660, 1720 cm⁻¹

EXAMPLE 2 ##STR11##

80 g (1.096 mol) of dimethylethylamine were added dropwise, withcooling, to 80 g (0.825 mol) of sulfamic acid suspended in 500 ml ofglacial acetic acid. When dissolution was complete, 80 ml (1.038 mol) ofdiketene were added, while cooling at 25°-35° C. After 16 hours, themixture was evaporated and the residue was stirred with acetone,whereupon crystallization took place. 110 g (43%), melting point 73°-75°C. The remainder of the reaction product, 128 g (50%), was obtained as asyrup from the mother liquor. ##STR12## IR (KBr) 1050, 1240, 1475, 1690,1730 cm⁻¹

EXAMPLE 3 ##STR13##

9.7 g (0.1 mol) of sulfamic acid in 100 ml of methylene chloride wereinduced to dissolve with 16 ml (0.12 mol) of triethylamine. Then, at 0°C., 8 ml (0.104 mol) of diketene were added dropwise. Stirring wascontinued at 0° C. for 2 hours and at room temperature for 2 hours.Then, the reaction product was precipitated by addition of hexane, andthe remaining syrup was washed with more hexane. 27-28 g (95.7-99%)remained after drying in vacuo; the syrup began to crystalline afterprolonged standing. ##STR14## IR (neat) 1040, 1230, 1450, 1650, 1670cm⁻¹

The following Examples 4-7 were carried out in a manner analogous tothat of Example 3; the result was:

EXAMPLE 4 ##STR15##

Yield: 92-97% ##STR16##

IR (CH₂ Cl₂) 1040, 1260, 1420, 1700, 1740 cm⁻¹

EXAMPLE 5 ##STR17##

Yield: 91-96% ##STR18##

IR (CH₂ Cl₂) 1040, 1250, 1420, 1700, 1740 cm⁻¹

EXAMPLE 6 ##STR19##

Yield 92-97% ##STR20## 4.3 (N.sup.⊕ -CH₂ -Ar), 7.35 (Ar),

IR (CH₂ Cl₂) 1040, 1260, 1270, 1430, 1470, 1700, 1740 cm⁻¹

EXAMPLE 7 ##STR21##

Yield 91-95%

NMR (CDCl₃) δ 1.3 and 1.4 (-CH₃), 2.2 (COCH₃) 3.5 (CH₂ -CO)

IR (CH₂ Cl₂) 1040, 1210, 1250, 1420, 1700, 1740 cm⁻¹

EXAMPLE8 ##STR22##

9.7 g (0.1 mol) of sulfamic acid were suspended in 100 ml of acetone,and 16 ml (0.12 mol) of triethylamine were added. When dissolution wasalmost complete, 8 ml (0.104 mol) of diketene were added dropwise at 0°C. Then, reaction was allowed to go to completion while stirring at roomtemperature, during which everything dissolved. After 16 hours, thereaction product was preciptate as a syrup using hexane, and the syrupwas further purified by stirring with hexane. 27-28 g (95.7-99%) ofsyrup remained after drying in vacuo, and this slowly crystallized onstanding. ##STR23##

IR (neat) 1040, 1230, 1450, 1670 cm⁻¹

EXAMPLE 9 ##STR24##

105 ml (0.16 mol) of a 40% strength aqueous solution oftetrabutylammonium hydroxide were added to 15.5 g (0.16 mol) of sulfamicacid in 10 ml of methanol and 50 ml of water. The mixture was thenevaporated to dryness. The residue was dissolved in 100 ml of methylenechloride, and the pH was adjusted to 9-10 with triethylamine. 10 ml ofdiketene were then added dropwise. After 12 hours, the pH was againadjusted to 9-10, and the addition of diketene was repeated. 16 hourslater, the mixture was evaporated, whereupon the residue crystallized.The paste of crystals was filtered off with suction and washed withethyl acetate and ether. 34.6 g (52%) melting point: 97-98° C. ##STR25##

IR (CH₂ Cl₂) 890, 1040, 1255, 1410 cm⁻¹.

EXAMPLE 10 ##STR26##

19.4 g (0.2 mol) of sulfamic acid and 15.4 ml (0.2 mol) of diketene in200 ml of methylene chloride were initially introduced at 0° C. Whilecooling and stirring, 29 ml (0.21 mol) of triethylamine were addeddropwise within 45 min. The reaction mixture was subsequently stirred 0°C. for 30 min and then allowed to stand overnight at room temperature.After evaporating off the solvent and drying in vacuo, the reactionproduct was obtained as a syrup. It was crystallized from acetone. 53-56g (94-99%); melting point 55°-58° C. ##STR27##

IR (neat) 1040, 1230, 1450, 1670 cm⁻¹

EXAMPLE 11 ##STR28##

19.4 g (0.2 mol) of sulfamic acid, 15.4 ml (0.2 mol) of diketene and1.14 ml (0.02 mol) of glacial acetic acid in 100 ml of methylenechloride were initially introduced at 0° C. While cooling and stirring,29 ml (0.21 mol) of triethylamine were added dropwise within min. Thereaction mixture was subsequently stirred at 0° C. for 30 min and thenallowed to stand overnight at room temperature. After evaporating offthe solvent, the residue was washed with diethyl ether and then dried invacuo. It was crystallized from acetone. 52-5 g (92-97.5%) melting point55-58° C. ##STR29##

IR (neat) 1040, 1230, 1450, 1670 cm⁻¹

EXAMPLE 12 ##STR30##

15.1 ml (120 mmol) of N,N-dimethylaniline were added to 9.7 g (100 mmol)of sulfamic acid in 100 ml of glacial acetic acid, and the mixture wasstirred until dissolution was complete. 8 ml (104 mmol) of diketene werethen added. After 16 hours, a further 2 ml of diketene were added to thesolution. When the diketene had disappeared, the mixture was evaporatedand the product was precipitated by stirring with ether.

Yield: 88-92% ##STR31##

IR (CH₂ Cl₂) 1040, 1250, 1430, 1700, 1740 cm⁻¹

EXAMPLE 13 ##STR32##

10 ml of diketene and 1 ml of pyridine were added to a suspension of11.4 g (100 mmol) of ammonium sulfamate in 100 ml of glacial aceticacid, while stirring vigorously. After 17 hours, the final product wasfiltered off with suction. 17 g =86%, decomposition above about 125° C.

EXAMPLE 14 ##STR33##

19.4 g (0.2 mol) of sulfamic acid in 200 ml of CH₂ Cl₂ were neutralizedwith 28 ml (0.2 mol) of diisopropylamine. After addition of 0.81 ml (10mmol) of pyridine, 15.4 ml (0.2 mol) of diketene were added dropwise at0° C. The reaction mixture was subsequently stirred at 0° C. for 30minutes and then allowed to stand overnight at room temperature. Afterevaporating off the solvent and drying in vacuo, the reaction productwas obtained as a syrup. 45-48 g =80-85%

IR (neat) 1040, 1280, 1450, 1670 cm⁻¹

EXAMPLE 15 ##STR34##

19.4 g (0.2 mol) of sulfamic acid in 100 ml of DMF were neutralized with21 ml (0.2 mol) of tert.-butylamine. After addition of 0.81 ml (10 mmol)of pyridine, 15.4 ml (0.2 mol) of diketene were added dropwise at 15° C.The mixture was then stirred at room temperature for 3 hours. Forworking-up, the reaction product was precipitated with 500 ml of diethylether. For purification, the syrup was stirred with acetone.

Yield: 42 g =83%

IR (neat) 1035, 1230, 1450, 1670 cm⁻¹

[B] Examples of carrying out process (steps b) and (c):

EXAMPLE 1

12.7 g (50 mmol) of dimethylethylammonium acetoacetamide-N-sulfonate in110 ml of methylene chloride were added dropwise to 8 ml (200 mmol) ofliquid SO₃ in 100 ml of CH₂ Cl₂ at -30° C., stirring vigorously, within60 minutes. 30 minutes later, 50 ml of ethyl acetate and 50 g of icewere added to the solution. The organic phase was separated off, and theaqueous phase was extracted twice more with ethyl acetate. The combinedorganic phases were dried over sodium sulfate, evaporated and theresidue was dissolved in methanol. On neutralization of the solutionwith methanolic KOH, the potassium salt of6-methyl-3,4-dihydro-1,2,3-oxathiazin-4-one 2,2-dioxide precipitatedout. 7.3 g =73%.

EXAMPLE 2

12.7 g (50 mmol) of dimethylethylammonium acetoacetamide-N-sulfonate in110 ml of CH₂ Cl₂ were added dropwise, within 60 minutes, to 8 ml (200mmol) of liquid SO₃ in 50 ml of SO₂ at -30° C., stirring vigorously. 30minutes later, after the evaporation of the SO₂, 50 ml of ethyl acetateand 50 g of ice were added to the solution. The organic phase wasseparated off, and the aqueous phase was extracted twice more with ethylacetate. The combined organic phases were dried over sodium sulfate,evaporated and the residue was dissolved in methanol. On neutralizationof the solution with methanolic KOH, the potassium salt of6-methyl-3,4-dihydro-1,2,3-oxathiazin-4-one 2,2-dioxide precipitatedout.

8.3 g =83%.

EXAMPLE 3

12.7 g (50 mmol) of dimethylethylammonium acetoacetamide-N-sulfonate in110 ml of CH₂ Cl₂ were added dropwise to 12 ml (300 mmol) of liquid SO₃in 100 ml of CH₂ Cl₂ at -30° C., stirring vigorously, within 60 minutes.30 minutes later, 50 ml of ethyl acetate and 10 g of ice were added tothe solution. The organic phase was separated off, and the aqueous phasewas extracted twice more with ethyl acetate. The combined organic phaseswere dried over sodium sulfate, evaporated and the residue was dissolvedin methanol. On neutralization of the solution with methanolic KOH, thepotassium salt of -methyl-3,4-dihydro-1,2,3-oxathiazin-4-one 2,2-dioxideprecipitated out. 7.6 g =76%

EXAMPLE 4

4.24 g (16.7 mmol) of dimethylethylammonium acetoacetamide-N-sulfonatein 35 ml of CH₂ Cl₂ were added dropwise within 20 minutes to 4 ml (100mmol) of liquid SO₃ in 100 ml of CH₂ Cl₂ at -30° C., stirringvigorously. Then 4 ml (100 mmol) of SO₃ were added to the solution,followed by another 4.24 g (16.7 mmol) of dimethylethylammoniumacetoacetamide-N-sulfonate in 35 ml of CH₂ Cl₂ added dropwise within 20minutes at -30° C. stirring vigorously. The addition of 4 ml (100 mmol)of SO₃ was then repeated. Then, 4.24 g (16.6 mmol) ofdimethylethylammonium acetoacetamide-N-sulfonate in 35 ml of CH₂ Cl₂were added dropwise within 20 minutes at -30° C., stirring vigorously.20 minutes later, the mixture was worked up as in Example 1.

8 7 g =87%.

EXAMPLE 5

12.7 g (50 mmol) of dimethylethylammonium acetoacetamide-N-sulfonate in110 ml of CH₂ Cl₂ were added dropwise within 60 minutes to 2.4 ml (60mmol) of SO₃ in 100 ml of CH₂ Cl₂ at -25° C., stirring vigorously. Overthe same period, 2.4 ml (60 mmol) of SO₃ were added on each occasionafter 12, 24, 36 and 48 minutes. 20 minutes later, the m1xture wasworked up as 1n Example 1.

8.8 g =88%.

EXAMPLE 6

The process was carried out as in Example 5, but 2.4 ml (60 mmol) of SO₃in 50 ml of SO₂ were introduced at the start.

8.8 g =88%.

EXAMPLE 7

12.8 g (160 mmol) of solid SO₃ were dissolved in 150 ml of CH₂ Cl₂ .After the solution had been cooled to -45°/-55° C., 8.4 g (26 mmol) oftripropylammonium acetoacetamide-N-sulfonate in 25 ml of CH₂ Cl₂ wereadded dropwise within 60 minutes. After 4 hours at -45°/-55° C., themixture was worked up as in Example 1. 2.8 g =54%.

In Examples 8-12, the reaction solutions from the reaction of diketene,sulfamic acid and triethylamine were used directly.

EXAMPLE 8

125 ml of triethylammonium acetoacetamide-N-sulfonate solution (0.1 mol;CH₂ Cl₂ ) were added dropwise, within 60 minutes, to 20 ml (500 mmol) ofliquid SO₃ in 500 ml of CH₂ Cl₂ at -30° C., stirring vigorously. After afurther 60 minutes at -30° C., the mixture was worked up as in Example1.

17.1 g =85%.

EXAMPLE 9

25 ml of triethylammonium acetoacetamide-N-sulfonate solution (0.1 mol;CH₂ Cl₂ ) were initially introduced into 250 ml of CH₂ Cl₂ at -30° C. 20ml (500 mmol) of liquid SO₃ dissolved in 250 ml of CH₂ Cl₂ were addedwithin 60 minutes. After a further 60 minutes at -30° C., the mixturewas worked up as in Example 1.

14.9 g =74%.

EXAMPLE 10

125 ml of triethylammonium acetoacetamide-N-sulfonate solution (0.1 mol;CH₂ Cl₂ ) were added dropwise, within 60 minutes, to 4.8 ml (120 mmol)of liquid SO₃ in 500 ml of CH₂ Cl₂ at -25° C. Four more portions of 4.8ml (120 mmol) of liquid SO₃ were added at intervals of 12 minutes. Afteranother 60 minutes at -25° C., the mixture was worked up as inExample 1. 18.3 g =91%.

EXAMPLE 11

50 ml of CH₂ Cl₂ at -30° C. were initially introduced. While cooling andstirring efficiently, a solution of 28.1 g (0.1 mol) of triethylammoniumacetoacetamide-Nsulfonate in 50 ml of CH₂ Cl₂ , and 24 ml of liquid SO₃in 50 ml of CH₂ Cl₂ , were simultaneously and steadily added dropwisewithin 30 min. After another 30 min at -25° C. to -30° C., 110 ml ofwater were cautiously added dropwise at the same temperature. The CH₂Cl₂ was then removed by distillation, and the reaction product wasextracted with 80 ml of i-butyl acetate. 20 ml of water were then addedto the organic phase and, while stirring vigorously, the pH was adjustedto 0.84-0.87 (pH meter, glass electrode: Ingold 405-60-S7) with 4 n KOH.After separation and extraction of the aqueous phase with 20 ml ofi-butyl acetate, 15 ml of water were added to the combined i-butylacetate phases and neutralized to pH 5-7 with 4 n KOH, while stirring.The partially precipitated K salt was filtered off with suction and thencombined with the aqueous phase of the filtrate. Evaporation of thewater in vacuo provided 18.1 g =90% of sweetener.

EXAMPLE 12

50 ml of CH₂ Cl₂ at -30° C. were initially introduced. Then a solutionof 28.1 g (0.1 mol) of triethylammonium acetoacetamide-N-sulfonate in 50ml of CH₂ Cl₂ , and 24 ml of liquid SO₃ in 50 ml of CH₂ Cl₂ , weresimultaneously and steadily run in while cooling intensively(isopropanol/dry ice). Immediate working-up as in EXAMPLE 11(extractant: isopropyl acetate) provided 17.9 g =89% of sweetener.

EXAMPLE 13

12.4 ml of 60% oleum (200 mmol of SO₃ ) were initially introduced into200 ml of CH₂ Cl₂ at -25° C. 62.5 ml of triethylammoniumacetoacetamide-N-sulfonate solution (50 mmol; CH₂ Cl₂ ) were addeddropwise within 30 minutes. After a further 60 minutes at -25°C., themixture was worked up as in Example 1.

4.7 g =47%.

EXAMPLE 14

8 ml (200 mmol) of liquid SO₃ were cautiously added to 200 ml ofcollidine at -30° C. Then 16.2 g (50 mmol) of tripropylammoniumacetoacetamide-N-sulfonate were added, and the reaction mixture washeated at about 100° C. for 20 hours. Most of the collidine was thenremoved by distillation in vacuo, and the residue was taken up in ethylacetate. After acidification with sulfuric acid, the aqueous phase wasthoroughly extracted with ethyl acetate. The organic phases were driedover Na₂ SO₄ and evaporated in vacuo. The residue was taken up inmethanol and neutralized with methanolic potassium hydroxide solution.The precipitated sweetener was filtered off with suction and dried. 2.2g =22%.

COMPARISON EXAMPLE

35.42 g (250 mmol) of P₂ O₅ were initially introduced into 250 ml of CH₂Cl₂ At -25° C., 62.5 ml of triethylammonium acetoacetamide-N-sulfonatesolution in CH₂ Cl₂ , with a sulfonate content of 0.05 mol, were addeddropwise within 60 minutes. After a further 60 minutes at -25° C., themixture was worked up as in Example B-1. No6-methyl-3,4-dihydro-1,2,3-oxathiazin-4-one 2,2-dioxide or its potassiumsalt could be detected in the reaction product by thin-layerchromatography.

We claim:
 1. A process for the preparation of6-methyl-3,4-dihydro-1,2,3-oxathiazin-4-one 2,2-dioxide and itsnon-toxic salts by ring closure of an acetoacetamide derivative, whichcomprises using as the acetoacetamide derivativeacetoacetamide-N-sulfonic acid or its salts, and carrying out the ringclosure by the action of at least the approximately equimolar amount ofSO₃ where appropriate in an inert inorganic or organic solvent, andthen, where appropriate, also neutralizing with a base the6-methyl3,4-dihydro-1,2,3-oxathiazin-4-one 2,2-dioxide which is producedin the form of the acid in this reaction.
 2. The process as claimed inclaim 1, wherein the SO₃ is used in a molar excess of up to about20-fold, preferably about 3- to 10-fold, in particular about 4-to7-fold, relative to the acetoacetamide-N-sulfonic acid (salts).
 3. Theprocess as claimed in claim 1, wherein the inert inorganic solvent usedis liquid SO₂ , and the inert organic solvent used is at least onesolvent from the following group:halogenated aliphatic hydrocarbons,preferably having up to 4 carbon atoms, esters of lower alochols andcarbonic acid, preferably methyl and ethyl carbonate, lowernitroalkanes, preferably having up to 4 carbon atoms, collidine andsulfolane.
 4. The process as claimed in claim 1, wherein the ringclosure reaction is carried out at temperatures between about -70° and+175° C., preferably between about -40° and +10° C.
 5. The process asclaimed in claim 1, wherein the6-methyl-3,4-dihydro-1,2,3-oxathiazin-4-one 2,2-dioxide, which isproduced in the form of the acid, is extracted from the sulfuric acidreaction medium using a halogenated solvent or an ester of carbonic acidor of an organic carboxylic acid, and, where appropriate, neutralizingwith a base the sulfuric acid which has been carried over.